This application is for a Research Scientist Award to support the research in the broad category of the mechanism of action of ethanol. The approach used is that of genetic animal models of various actions of ethanol and is built upon the assumption that the genetic risk factors in human alcoholism are in some way due to genetic variations in the reactions of individuals to the actions of ethanol. While the genetic variabilities in alcohol actions between man and animals need not be identical, those found in animals serve two functions. First, genetic polymorphisms discovered in animals are a starting point in studies of humans and, second, the availability of genetic animals models provides a tool by which ethanol effects may be dissected at the cellular and molecular level. The axiom that guides all of this work is that once a process is understood in sufficient detail, the chances of interfering or altering that process are much improved. The ultimate aim of the research is to provide improved prevention and treatment procedures or therapeutic agents for individuals with alcohol abuse or alcoholism. The grant outlines the approach in three areas. 1. Selective breeding of rats for initial sensitivity to ethanol and analysis of the effects of ethanol in these animals. 2. Study of acute tolerance in mice selected for initial sensitivity to ethanol. 3. Study of the flushing reactions in Native American populations and correlations of these reactions with incidence of alcoholism and alcohol drinking practices.